Osteosarcoma (OS) is the most common bone cancer of children under 20 years of age in the United States and Canada, with about 430 news cases diagnosed each year. The close correlation of OS incidence with the childhood growth curve, the earlier peak in incidence in females, and the frequent occurrence of OS in the long bones of the leg suggest that the etiology of pediatric OS is linked to bone growth. The implication of this descriptive epidemiology is that children with a more rapid or sustained growth spurt have a higher risk of OS. However, the association of OS with height is inconsistent and other factors related to growth have shown no consistent pattern. As the timing and extent of adolescent bone growth are under substantial genetic control a genetic investigation of OS etiology is appropriate. Using the resources of the Children's Oncology Group (COG), we propose to conduct the largest and most comprehensive genetic investigation of pediatric OS to date. This study will employ the case-parent triad design to study main effects of genes in the insulin-like growth factor/growth hormone axis and estrogen metabolism pathways, which relate to bone growth, and two genes involved in DNA integrity (RECQL2, RECQL4). Gene x environment (GxE) and gene x gene (GxG) interaction will also be explored. Common single nucleotide polymorphisms (SNPs) and other variants will be chosen for study that meet any of the following criteria: 1) designation as a haplotype-tagging SNP in public databases, 2) coding non-synonymous SNPs with deleterious function predicted by sequence homology algorithms, 3) effect of variant on protein function or expression reported in the literature. About 500 children diagnosed with OS at North American COG institutions will be enrolled along with their parents over a three-year period. Buccal cells will be collected through the mail for genotyping;stored blood or tissue samples will be collected for the small minority of deceased cases. Data concerning diet, physical activity, family health history, and anthropometries will also be collected through mailed surveys of parents and children.